Both pharmacological studies on human patients and the analysis of animal models indicate that many forms of epilepsy involve dysfunction of neuron systems that use gamma-aminobutyric acid (GABA) as a principal neurotransmitter. The purpose of this project is to use recombinant DNA techniques to isolate the genes coding for two proteins that are central to GABA-ergic functions -- glutamic acid decarboxylase (GAD) and GABA receptor (GABA-R). Altered structures of these genes may be responsible for the inheritance of some forms of epilepsy. This project will test three hypotheses: 1. A gene coding for a GAD or GABA-R polypeptide is the site of the genetic lesion in Juvenile Myoclonic Epilepsy (JME). 2. The structure and expression of one of the GAD or GABA-R genes is altered in the existing genetic animal models of epilepsy (seizure-sensitive gerbils, audiogenic seizure sensitive mice, and tottering mice). 3. Epilepsy can be produced in mice by specifically blocking the expression of the genes for GAD or GABA-R. In order to test these hypotheses, we propose to employ recombinant DNA techniques now in use in this laboratory. We propose to isolate the genes for GAD and GABA-R and to study their structure and inheritance both in experimental animals and in families with JME. We will also attempt to develop new methods to study the functions of the candidate genes in tissue culture cells and in transgenic mice.